Silencing a Metabolic Oncogene

Many human cancers, particularly gliomas and acute myelogenous leukemia (AML), contain mutations in the genes IDH1 or IDH2, which encode two isoforms of the metabolic enzyme isocitrate dehydrogenase (1, 2). These mutant enzymes produce the (R)-enantiomer of 2-hydroxyglutaric acid [(R)-2HG], a molecule that inhibits histone- and DNA-modifying enzymes, thereby altering gene expression and promoting the acquisition of malignant features (3–5). Reports by Losman et al. (6) as well as by Wang et al. (7) and Rohle et al. (8) on pages 622 and 626 of this issue, respectively, find that inhibitors of the mutant forms of IDH1/2 suppress the growth of (R)-2HG–producing tumor cells (6–8). The findings imply that curtailing (R)-2HG supply normalizes gene expression and reverses malignancy.